ABSTRACT Functional pain syndromes (FPS) affect over 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to reduced activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ?low COMT activity? genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhanced pain following repeated stress. In subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral ?-adrenergic receptors through the release of pro-inflammatory cytokines (e.g., TNF? and IL-6) in plasma, and maintained by neuroplastic changes in the central nervous system, characterized by increased expression of TNF? and increased activation of glia and nociceptors in the spinal cord. Together, these findings suggest that heightened adrenergic tone promotes pain, inflammation, and neuroinflammation in patients with FPS. Acupuncture and the fish oil derivative DHA are recommended treatments for FPS, however their mechanistic effects on inflammation and neuroinflammation associated with deficiencies in COMT have remained unstudied. We hypothesize that acupuncture, DHA, and the DHA-derived resolvin D1 (RvD1) each produce beneficial effects in preventing and treating functional pain exacerbated by stress via modulating immune response and nociceptor activity. Preliminary data reveal that ST36 acupuncture reverses COMT-dependent pain and corresponding activation of glial cells in the spinal cord. Additional data reveal that DHA reverses COMT- dependent pain and nociceptor activity exacerbated by stress. The proposed studies will extend this work to 1) determine the time course for the development, maintenance, and resolution of functional pain (e.g., mechanical allodynia and locomotor activity), inflammation (e.g., cytokines and activated macrophages and T cells in plasma), and neuroinflammation (e.g., cytokines in CSF and activated glia in spinal cord) caused by low COMT activity and exacerbated by stress, 2) test the effects of electroacupuncture, DHA, and RvD1 in preventing and reversing functional pain, inflammation, and neuroinflammation in the absence or presence of stress, and 3) test the effects of electroacupuncture (versus manual acupuncture), DHA, and RvD1 in reversing increased activity of mechanosensitive and thermosensitive nociceptors that drive functional pain in the absence and presence of stress. Results from these studies will advance our knowledge about the consequences of heightened catecholamine tone on immune function and determine the utility of complementary medicine therapies to restore immune homeostasis and alleviate functional pain.